Current status of gene therapy research in polyglutamine spinocerebellar ataxias

Polyglutamine spinocerebellar ataxias (PolyQ SCAs) are a group of 6 rare autosomal dominant diseases, which arise from an abnormal CAG repeat expansion in the coding region of their causative gene. These neurodegenerative ataxic disorders are characterized by progressive cerebellar degeneration, which translates into progressive ataxia, the main clinical feature, often accompanied by oculomotor deficits and dysarthria. Currently, PolyQ SCAs treatment is limited only to symptomatic mitigation, and no therapy is available to stop or delay the disease progression, which culminates with death. Over the last years, many promising gene therapy approaches were investigated in preclinical studies and could lead to a future treatment to stop or delay the disease development. Here, we summed up the most promising of these therapies, categorizing them in gene augmentation therapy, gene silencing strategies, and gene edition approaches. While several of the reviewed strategies are promising, there is still a gap from the preclinical results obtained and their translation to clinical studies. However, there is an increase in the number of approved gene therapies, as well as a constant development in their safety and efficacy profiles. Thus, it is expected that in a near future some of the promising strategies reviewed here could be tested in a clinical setting and if successful provide hope for SCAs patients.Foundation (FCT) project (ALG-01-0145-FEDER-29480)info:eu-repo/semantics/publishedVersio

Anaplastic thyroid cancer

Globally, thyroid cancer accounts for 2 % of all cancer diagnoses, and can be classified as well-differentiated or undifferentiated. Currently, differentiated thyroid carcinomas have good prognoses, and can be treated with a combination of therapies, including surgical thyroidectomy, radioactive iodine therapy and hormone-based therapy. On the other hand, anaplastic thyroid carcinoma, a subtype of undifferentiated thyroid carcinoma characterized by the loss of thyroid-like phenotype and function, does not respond to either radioactive iodine or hormone therapies. In most cases, anaplastic thyroid carcinomas are diagnosed in later stages of the disease, deeming them inoperable, and showing poor response rates to systemic chemotherapy. Recently, treatment courses using multiple-target agents are being explored and clinical trials have shown very promising results, such as overall survival rates, progression-free survival and tumor shrinkage. This review is focused on thyroid carcinomas, with particular focus on anaplastic thyroid carcinoma, exploring its undifferentiated nature. Special interest will be given to the treatment approaches currently available and respective obstacles or drawbacks. Our purpose is to contribute to understand why this malignancy presents low responsiveness to current treatments, while overviewing novel therapies and clinical trials

Anaplastic thyroid cancer: how far can we go?

Globally, thyroid cancer accounts for 2 % of all cancer diagnoses, and can be classified as well-differentiated or undifferentiated. Currently, differentiated thyroid carcinomas have good prognoses, and can be treated with a combination of therapies, including surgical thyroidectomy, radioactive iodine therapy and hormone-based therapy. On the other hand, anaplastic thyroid carcinoma, a subtype of undifferentiated thyroid carcinoma characterized by the loss of thyroid-like phenotype and function, does not respond to either radioactive iodine or hormone therapies. In most cases, anaplastic thyroid carcinomas are diagnosed in later stages of the disease, deeming them inoperable, and showing poor response rates to systemic chemotherapy. Recently, treatment courses using multiple-target agents are being explored and clinical trials have shown very promising results, such as overall survival rates, progression-free survival and tumor shrinkage. This review is focused on thyroid carcinomas, with particular focus on anaplastic thyroid carcinoma, exploring its undifferentiated nature. Special interest will be given to the treatment approaches currently available and respective obstacles or drawbacks. Our purpose is to contribute to understand why this malignancy presents low responsiveness to current treatments, while overviewing novel therapies and clinical trials.This research was funded by Fundação para a Ciência e a Tecnologia (FCT) through the Project Reference UID/DTP/04138/2019.info:eu-repo/semantics/publishedVersio

Anaplastic thyroid cancer: How far can we go?

This research was funded by Fundacao para a Ciencia e a Tecnologia (FCT) through the Project Reference UID/DTP/04138/2019.Globally, thyroid cancer accounts for 2 % of all cancer diagnoses, and can be classified as well-differentiated or undifferentiated. Currently, differentiated thyroid carcinomas have good prognoses, and can be treated with a combination of therapies, including surgical thyroidectomy, radioactive iodine therapy and hormone-based ther-apy. On the other hand, anaplastic thyroid carcinoma, a subtype of undifferentiated thyroid carcinoma character-ized by the loss of thyroid-like phenotype and function, does not respond to either radioactive iodine or hormone therapies. In most cases, anaplastic thyroid carcinomas are diagnosed in later stages of the disease, deeming them inoperable, and showing poor response rates to systemic chemotherapy. Recently, treatment courses using multi-ple-target agents are being explored and clinical trials have shown very promising results, such as overall survival rates, progression-free survival and tumor shrinkage. This review is focused on thyroid carcinomas, with particular focus on anaplastic thyroid carcinoma, exploring its undifferentiated nature. Special interest will be given to the treatment approaches currently available and respective obstacles or drawbacks. Our purpose is to contribute to understand why this malignancy presents low responsiveness to current treatments, while overviewing novel therapies and clinical trials.publishersversionpublishe

Síndromes liquóricas em pacientes com comprometimento agudo da consciência

We reviewed the laboratorycards of 200 analysis of cerebrospinal fluid (CSF) performed to evaluate acute alterations of consciousness in adult patients attended in a neurological emergency room. 61% were men; the mean age was 46 years. The most common clinical data were infective and neurologic. The CSF was abnormal in 149 (74.5%) patients and the most common syndromes were: compressive (21%), hemorrhagic (11.5%), viral (8.5%), septic (7.5%), moderate hyperglycorrachia (6.5%), hydroelectrolytic disturbances (5.5%). There were some statistically significant correlations between CSF syndromes and clinical data: septic syndrome and fever and meningeal signs, hemorrhagic syndrome and headache and meningeal signs, CSF hydroelectrolytic disturbance syndrome and seizures, severe hyperproteinorrachia and headache, fever, meningeal signs and vomiting, moderate hyperproteinorrachia and age over 65 and male sex. We classified the abnormal results in two groups: 1 - sufficient for an immediate clinical decision; 2 - nonspecific. The former group was found in 27.5% of the patients and in 36.9% of the abnormal CSF results. In patients attending to neurologic emergency rooms with acute alterations of consciousness, the examination of the CSF frequently could contribute to an etiologic diagnosis. It must be performed after a rigorous clinical evaluation of the patient.Nós revisamos os registros de 200 exames de líquido cefalorraquidiano (LCR) realizados para avaliar alterações agudas da consciência em pacientes adultos atendidos em um pronto-socorro neurológico. 61% eram homens e a idade média era 46 anos. Os dados clínicos mais comuns foram infecciosos e neurológicos. O LCR foi anormal em 149 (74,5%) pacientes e as síndromes mais comuns foram: compressiva (21%), hemorrágica (11,5%), viral (8,5%), séptica (7,5%), hiperglicorraquia moderada (6,5%), distúrbio hidro-eletrolítico (5,5%). Nós classificamos os resultados anormais em dois grupos: 1 - suficientes para uma decisão clínica imediata; 2 - inespecíficos. O primeiro grupo foi encontrado em 27,5% dos pacientes e em 36,9% dos resultados anormais. Houve algumas correlações estatisticamente significantes entre dados clínicos e síndromes liquóricas: síndrome séptica e febre e sinais meníngeos, síndrome hemorrágica e cefaléia e sinais meníngeos, distúrbio hidro-eletrolítico no LCR e convulsões, hiperproteinorraquia acentuada e cefaléia, febre, sinais meníngeos e vômitos, hiperproteinorraquia moderada e idade acima de 65 anos e sexo masculino. Em pacientes atendidos em pronto-socorro neurológico com alterações agudas da consciência, o exame do LCR frequentemente pode contribuir para um diagnóstico etiológico. Deve ser solicitado após rigorosa avaliação clínica do paciente.Universidade Federal de São Paulo (UNIFESP), Escola Paulista de Medicina (EPM) Department of NeurologyUNIFESP, EPM, Department of NeurologySciEL

Wilson's disease in southern Brazil: a 40-year follow-up study

BACKGROUND: Long-term data on the clinical follow-up and the treatment effectiveness of Wilson's disease are limited because of the low disease frequency. This study evaluated a retrospective cohort of Wilson's disease patients from southern Brazil during a 40-year follow-up period. METHODS: Thirty-six Wilson's disease patients, diagnosed from 1971 to 2010, were retrospectively evaluated according to their clinical presentation, epidemiological and social features, response to therapy and outcome. RESULTS: Examining the patients' continental origins showed that 74.5% had a European ancestor. The mean age at the initial symptom presentation was 23.3 ± 9.3 years, with a delay of 27.5 ± 41.9 months until definitive diagnosis. At presentation, hepatic symptoms were predominant (38.9%), followed by mixed symptoms (hepatic and neuropsychiatric) (30.6%) and neuropsychiatric symptoms (25%). Kayser-Fleischer rings were identified in 55.6% of patients, with a higher frequency among those patients with neuropsychiatric symptoms (77.8%). Eighteen patients developed neuropsychiatric features, most commonly cerebellar syndrome. Neuroradiological imaging abnormalities were observed in 72.2% of these patients. Chronic liver disease was detected in 68% of the patients with hepatic symptoms. 94.2% of all the patients were treated with D-penicillamine for a mean time of 129.9 ± 108.3 months. Other treatments included zinc salts, combined therapy and liver transplantation. After initiating therapy, 78.8% of the patients had a stable or improved outcome, and the overall survival rate was 90.1%. CONCLUSION: This study is the first retrospective description of a population of Wilson's disease patients of mainly European continental origin who live in southern Brazil. Wilson's disease is treatable if correctly diagnosed, and an adequate quality of life can be achieved, resulting in a long overall survival

Tick-borne diseases in asymptomatic cattle from São Miguel Island, Azores – A clinical perspective

Tick-borne diseases in asymptomatic cattle from São Miguel Island, Azores – A clinical perspective Introduction/Background: The Azores archipelago is one of the regions with the highest cattle production, in Portugal. Outbreaks of tick-borne (TB) diseases have been reported by local field veterinarians and different tick species are described in São Miguel. At this study, we decided to investigate the presence of some of these agents in asymptomatic cattle, in S. Miguel. Materials & methods: In October 2019, 10 blood samples from each of 10 farms were randomly selected. Species belonging to the Babesia/Theileria and Anaplasma/ Ehrlichia genus were tested by PCR screening. Results: There were 45 positive samples later confirmed as species belonging to the Theileria orientalis group (45/100, 45%), in 9 farms (9/10, 90%) and it was also possible to identify Anaplasma bovis, in 2 animals, at two farms (2/10, 20%). Discussion: As far as we were able to verify, this is the first reference to the presence of these agents in S. Miguel. However, although asymptomatic, the repercussions associated with these infections are probably being underestimated or confused with other health problems. Since ixodids were not found in cows, other factors may be contributing to the high percentage of positive samples found, such as poor management practices. This is clearly an interesting subject for further investigation, as a better understanding of the life cycle of these parasites will contribute to their control

A step forward

Funding: Authors gratefully acknowledge Fundação para a Ciência e a Tecnologia (FCT) through projects UIDB/00645/2020, UIDB/04138/2020, PTDC/MED-QUI/31721/2017, UIDP/04138/2020 and Lusófona University, ULHT. Authors are also thankful to FCT/MCTES for the financial support to CESAM (UIDP/50017/2020, UIDB/50017/2020), through national funds.Anaplastic thyroid carcinoma (ATC) is a very rare subtype of thyroid carcinoma and one of the most lethal malignancies. Poor prognosis is mainly associated with its undifferentiated nature, inoperability, and failing to respond to the typically used therapies for thyroid cancer. Photothermal Therapy (PTT) entails using light to increase tissues’ temperature, leading to hyperthermia-mediated cell death. Tumours are more susceptible to heat as they are unable to dissipate it. By using functionalized gold nanoparticles (AuNPs) that transform light energy into heat, it is possible to target the heat to the tumour. This study aims to formulate ATC-targeted AuNPs able to convert near-infrared light into heat, for PTT of ATC. Different AuNPs were synthetized and coated. Size, morphology, and surface plasmon resonances band were determined. The optimized coated-AuNPs were then functionalized with ligands to assess ATC’s specificity. Safety, efficacy, and selectivity were assessed in vitro. The formulations were deemed safe when not irradiated (>70% cell viability) and selective for ATC. However, when irradiated, holo-transferrin-AuNPs were the most cytotoxic (22% of cell viability). The biodistribution and safety of this formulation was assessed in vivo. Overall, this novel formulation appears to be a highly promising approach to evaluate in a very near future.publishersversionpublishe

Differential effects of swimming training on neuronal calcium sensor-1 expression in rat hippocampus/cortex and in object recognition memory tasks

AbstractPhysical activity has been proposed as a behavioral intervention that improves learning and memory; nevertheless, the mechanisms underlying these health benefits are still not well understood. Neuronal Calcium Sensor-1 (NCS-1) is a member of a superfamily of proteins that respond to local Ca2+ changes shown to have an important role in learning and memory. The aim of the present study was to investigate the effects of swimming training on NCS-1 levels in the rat brain after accessing cognitive performance. Wistar rats were randomly assigned to sedentary (SG) or exercised groups (EG). The EG was subject to forced swimming activity, 30min/day, 5 days/week, during 8 weeks. Progressive load trials were performed in the first and last week in order to access the efficiency of the training. After the 8 week training protocol, memory performance was evaluated by the novel object preference and object location tasks. NCS-1 levels were measured in the cortex and hippocampus using immunoblotting. The EG performed statistically better for the spatial short-term memory (0.73±0.01) when compared to the SG (0.63±0.02; P<0.05). No statistically significant exercise-effect was observed in the novel object preference task (SG 0.65±0.02 and EG 0.68±0.02; p>0.05). In addition, chronic exercise promoted a significant increase in hippocampal NCS-1 levels (1.8±0.1) when compared to SG (1.17±0.08; P<0,05), but had no effect on cortical NCS-1 levels (SG 1.6±0.1 and EG 1.5±0.1; p>0.05). Results suggest that physical exercise would modulate the state of the neural network regarding its potential for plastic changes: physical exercise could be modulating NCS-1 in an activity dependent manner, for specific neural substrates, thus enhancing the cellular/neuronal capability for plastic changes in these areas; which, in turn, would differentially effect ORM task performance for object recognition and displacement